Overexpression of human LCAT in mice (hL-Tg)increases HDL but paradoxically, decreases atherosclerosis. To evaluate whether the mouse enzyme, with different cholesteryl ester (CE)-fatty acid (FA) specificity (decreased 16:0/20:4 CE-FA ratio compared to human) reduces the atherogenic risk, we generated a new transgenic mouse model overexpressing mouse LCAT [mL-Tg; LCAT act= 79?2 nm/ml/h, CER=198?32 nm/ml/h)and compared them to controls [C; LCAT act=32?4 nm/ml/h, CER=118?9 nm/ml/h)and hL-Tg[LCAT act=3513?401 nm/ml/h, CER=225?16 nm/ml/h]. On a reg chow diet mL-Tg (n=16) lipids (in mg/dl) were: TC=170?10,TG=78?6, PL=209?8,CE=134?8,HDL-C=118?12; in C (n=10):TC=68?3,TG=68?4,PL=134?5, CE=54?3,HDL-C=70?3 and hL- Tg(n=11):TC=164?14, TG=58?5,PL=182?15, CE=133?12,HDL-C=94?7. mL-Tg had heterogeneous HDL with apoA-I and apoA-I/A-II HDL and decreased pre- beta-HDL. The catabolism of 131apoA-I HDL (FCR=2.22?0.08 d-1) and 3H-CE HDL (FCR=4.25?0.13 d-1)in mL-Tg was delayed (approximately 20%; p<0.02 both) compared to C. On a high-fat high-chol diet mL-Tg increased C(+137%), C(+110%), CE(+145%) and decreased HDL(-7%) compared to baseline (p<0.02; all) & increased TC(+22%) and CE(+28%) compared to C (p<0.05; both). Mean aortic lesion area (microm2) increased(4X) in mL- Tg(17x103) compared to C(4x103;p<0.0001). In summary: 1)In contrast to hL-Tg, minimal increase in mouse LCAT expression (LCAT act/CER increase 2X of C) decreased TC,PL,CE and HDL-C levels by 1.5-2.5X. 2)Delayed catabolism of apoA-I and HDL-CE leads to increase HDL in mL-Tg. 3)Despite increased HDL and altered CE-FA ratio, mL-Tg mice have increased (4X) atherosclerosis indicating that the CE-FA composition determined by the different specificities of mouse vs human LCAT does not modulate the atherogenic risk in LCAT-Tg. 4)Abnormal HDL metabolism indicates that impaired reverse cholesterol transport may lead to enhanced atherosclerosis in mLCAT-Tg.